1. Technical Field of the Invention
The present invention relates to dermatological/cosmetic compositions comprising, formulated into a physiologically acceptable medium, at least one retinoid, dispersed benzoyl peroxide and a gelling system which comprises at least two particular categories of compounds.
2. Description of Background and/or Related and/or Prior Art
The administration of several classes of active principles is a therapeutic tool that is frequently employed, especially for treating dermatological disorders.
Specifically, in the treatment of dermatitis it is known to administer corticosteroids such as, for example hydrocortisone, miconazole or betamethasone valerate, antihistamines (e.g., mizolastine) and/or keratolytic agents such as salicylic acid. Various anti-fungal agents such as allylamine derivatives, triazoles, anti-bacterial or anti-microbial agents such as, for example, antibiotics, quinolones and imidazoles are also conventionally combined in the treatment of dermatological diseases. Peroxides, D vitamins and retinoids are also described for the topical treatment of various pathologies associated with the skin or mucous membranes, in particular acne.
The combination of several local treatments (antibiotics, retinoids, peroxides, zinc) is also employed in dermatology to increase the effectiveness of the active principles and to decrease their toxicity (Cunliffe W. J., J. Dermatol. Treat., 2000, 11 (Suppl. 2), 513-514).
The multiple application of various dermatological products may be quite taxing and demanding for the patient.
The advantage is therefore understood in seeking to obtain a novel treatment that is effective on dermatological conditions, that has a stable composition offering good cosmetic quality, allowing a single application and administration that is pleasant for the patient.
However, the formulation of such a composition poses several problems.
Firstly, the effectiveness of benzoyl peroxide is linked to its decomposition when it is placed in contact with skin. Indeed, it is the oxidizing properties of the free radicals produced during this decomposition that result in the desired effect. Thus, in order to maintain an optimal effectiveness of the benzoyl peroxide, it is important to prevent its decomposition before use, that is to say during storage.
However, benzoyl peroxide is an unstable chemical compound which makes its formulation in finished products difficult.
The solubility and stability of benzoyl peroxide have been studied by Chellquist et al. in ethanol, propylene glycol and various mixtures of polyethylene glycol 400 (PEG 400) and water (Chellquist E. M. and Gorman W. G., Pharm. Res., 1992, Vol. 9: 1341-1346). Benzoyl peroxide proved to be particularly soluble in PEG 400 and ethanol.
This document furthermore specifies that the stability of benzoyl peroxide is strongly influenced by the chemical composition of the formulation and by the storage temperature.
Benzoyl peroxide is extremely reactive and degrades in solution at low temperature due to the instability of its peroxide bond.
The authors thus report that benzoyl peroxide in solution degrades more or less quickly in all the solvents studied, depending on the type of solvent and on its concentration.
The degradation times of benzoyl peroxide in PEG 400 (0.5 mg/g), in ethanol and in propylene glycol are respectively 1.4, 29 and 53 days at 40° C. Such a degradation does not allow the preparation of a product useful for sale.
Furthermore, it is known that benzoyl peroxide is more stable in water and propylene glycol when it is in suspension (i.e., in dispersed form), as it is not degraded after being kept for 90 days in these solvents.
Thus, to limit the problem of rapid instability of benzoyl peroxide in solution, it has proved advantageous to formulate the benzoyl peroxide in dispersed form.
Another difficulty to be overcome for preparing a composition comprising both benzoyl peroxide and a retinoid is that most retinoids are particularly sensitive to natural oxidation, to visible light and to ultraviolet light, and since benzoyl peroxide is a strong oxidizer the chemical compatibility of these compounds in one and the same formulation poses numerous stability problems from a physical and chemical viewpoint.
A study on the stability of two retinoids was carried out by combining two commercial products, one containing a retinoid (tretinoin or adapalene) and the second based on benzoyl peroxide (B. Martin et al., Br. J. Dermatol., (1998) 139, (suppl. 52), 8-11).
The presence of the formulation based on benzoyl peroxide causes a very rapid degradation of the oxidation-sensitive retinoids: it is calculated that 50% of the tretinoin is degraded in 2 hours and 95% in 24 hours. In the composition in which the retinoid is adapalene, no degradation of the adapalene was measured over 24 hours.
This study confirms that the benzoyl peroxide is degraded and degrades the oxidation-sensitive retinoids over time by gradually releasing benzoic acid into the initial products.
On the other hand, no indication was given regarding the physical stability of the two compositions brought together, nor on the therapeutic activity likely to be obtained at the end by combining the two active principles in the same composition.
Nothing would prompt these two active agents to be combined in order to obtain a stable gel-type composition, given that it was commonly known that the presence of benzoyl peroxide chemically and physically destabilized this type of composition.
However, it is clear that the too rapid degradation of benzoyl peroxide and the chemical degradation of the retinoids is undesirable insofar as it impairs the effectiveness of the composition containing them.
Furthermore, a finished product, in particular when it is a pharmaceutical or cosmetic composition, must maintain, throughout its shelf life, precise physicochemical criteria that make it possible to guarantee its pharmaceutical or cosmetic quality respectively. Among these criteria, it is necessary that the rheological properties be retained. They define the behavior and texture of the composition during application, but also the release properties of the active principle [1998 SFSTP Commission Report] and the homogeneity of the product when the active principles are present therein in the dispersed state.
In particular, the formulation of benzoyl peroxide and a retinoid in gel form is advantageous for topical treatments, such as those of acne, as it especially avoids maintaining a greasy feel on the skin.
Another difficulty to be overcome for preparing a composition especially comprising benzoyl peroxide, when it is in gel form, is that the gelling agents are destabilized by the benzoic acid released during the degradation of benzoyl peroxide.
Indeed, the most commonly used thickening agents for formulating these compositions with benzoyl peroxide are acrylic acid polymers (Carbomer).
However, the use of carbomers in aqueous gel-type compositions does not give good results in terms of chemical stability of benzoyl peroxide and in terms of rheological stability. As described by Bollinger (Bollinger, Journal of Pharmaceutical Science, 1977, Vol. 5), a loss of 5 to 20% benzoyl peroxide has been observed at the end of 2 months at 40° C. depending on the carbomer neutralizer used. Furthermore, the release of benzoic acid causes the depolymerization of the carbomers, causing a drop in viscosity which may result in phase separation.
This instability of benzoyl peroxide gels impairs their effectiveness and their cosmetic quality.
Therefore, the need remains to provide a physically stable gelled composition comprising benzoyl peroxide and a retinoid. However, nothing among the range of therapies proposed to one skilled in this art would suggest the combination, in the same composition, of benzoyl peroxide and a retinoid and several different gelling agents.